KR100417207B1 - Diaminopyrimidines, pharmaceutical compositions containing them and their use as antibacterial - Google Patents

Abstract

Diaminopyrimidines of general formula I <CHEM> wherein R<1> signifies hydrogen, R<2> signifies C3-5- omega -carboxyalkyl; R<3> signifies C1-5-alkyl; and their pharmaceutically acceptable acid addition salts have antibiotic properties and can be used in the control or prevention of infectious diseases.

Description

DIAMINOPYRIMIDINES, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND THEIR USE AS ANTIBACTERIAL BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a diaminopyrimidine compound,

The present invention relates to compounds of formula (I) and pharmaceutically acceptable acid addition salts thereof:

In this formula,

R ¹ is a straight chain C _5-10 -alkyl, branched chain C _3-5 -alkyl, C _3-6 -cycloalkyl or C _3-5 -ω-carboxyalkyl and R ² and R ³ are C _1-5- Alkyl;

R ¹ is hydrogen, R ² is C _3-5 -ω-carboxyalkyl, and R ³ is C _1-5 -alkyl.

These compounds have novel and useful antibiotic properties. They can be used for the treatment or prevention of infectious diseases. Specifically, they exhibit pronounced antimicrobial activity against opportunistic pathogens such as multi-resistant, gram-positive strains and Pneumocystis carinii . This compound may also be administered together with known antimicrobial active substances to exhibit a synergistic effect. Typical combination partners such as sulfonamides can be mixed in different ratios with the compounds of formula (I) or their salts.

It is an object of the present invention to provide compounds of formula (I) as such and as therapeutically active substances, esters and pharmacologically acceptable salts thereof which are readily hydrolyzable thereof; Agents based on these materials, optionally in combination with sulfonamides, and methods for their production; As medicaments and the use of these substances for the production of antimicrobial active agents; And methods for preparing the compounds of formula (I) and their pharmaceutically acceptable salts, and intermediates for their preparation.

The terms C _1-5 , C _3-5 and C _5-10 mean the number of carbon atoms in the corresponding group. Examples of C _{1-5 -alkyl} groups include methyl, ethyl, propyl, isopropyl, n-butyl and isomers thereof, and n-pentyl and isomers thereof. Examples of C _3-6 -cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of straight-chain C _{5-10 -alkyl} groups are n-pentyl, n-hexyl and n-heptyl. Examples of branched C _{3-5 -alkyl} groups are isopropyl, sec-butyl and amyl. A preferred C _3-5 -ω-carboxyalkyl group is ω-carboxypropyl.

Formula (I) Compounds of preferred group R ¹ is a straight chain C _5-10 a-cycloalkyl or C _3-5 -ω- carboxy alkyl-alkyl, branched C _3-5 -alkyl, C _3-6 .

The compound of formula (I) may be prepared by a) cyclizing a compound of formula (II), b) reacting a compound of formula (III) with guanidine, removing the protecting group present, I) may be prepared according to the invention by converting it into a pharmaceutically acceptable salt.

In this formula,

R ¹ , R ² and R ³ are as defined above, and X is a leaving group.

The cyclisation according to process a) is conveniently carried out, for example, in a suitable solvent such as, for example, N, N-diethylaniline, polyethylene glycol 400, nitrobenzene, ortho-dichlorobenzene or diphenyl ether, Heating the compound to, for example, about 180 to 220 &lt; 0 &gt;C; Can be carried out in a manner known per se by treating the compound of formula (II) with a silver and mercury salt in a chlorinated solvent at about 20 to 120 &lt; 0 &gt; C, see WK Anderson and EJ LaVoie Quot; J, Org. Chem., 38, 3832 (1973), Chem. Reviews 84, 221-223 (1984) and S. M. Daluge and P. M. Skonezny, European Patent No. 0051879 (November 11, 1981).

The reaction according to method b) can be carried out in a manner known per se [see, for example, P. S. Manchand et al., J. Org. Chem. 57, 3531-3535 (1992)]. Examples of leaving group X are alkoxy such as methoxy, arylamino such as anilino and morpholino.

The compounds of formula (I) together with the organic and inorganic acids form pharmaceutically acceptable acid addition salts. Examples of acid addition salts of the compounds of formula (I) include salts with inorganic acids such as hydrochloric acid, hydrohalic acids such as hydrogen bromide and hydrogen iodide, sulfuric acid, nitric acid and phosphoric acid; Organic sulfonic acids such as methanesulfonic acid, p-toluene-sulfonic acid and benzenesulfonic acid and the like, and salts with organic carboxylic acids such as acetic acid, tartaric acid, maleic acid, citric acid, benzoic acid , Salicylic acid, and ascorbic acid.

The compound of formula (I) containing a carboxyl group may also form a pharmaceutically acceptable salt having a base. Examples of salts of such compounds of formula (I) include alkali metal salts such as sodium and potassium salts, ammonium salts, organic bases such as diisopropylamine, benzylamine, dibenzylamine, triethanolamine, triethylamine, N, Dibenzylethylenediamine, salts with N-methylmorpholine, pyridine, piperazine, N-ethylpiperidine, N-methyl-D-glucamine and procain, or amino acids such as arginine and lysine of

Lt; / RTI &gt;

The compounds of formulas (II) and (III) are novel and are also an object of the present invention. These may be prepared according to the following reaction scheme (1), wherein R ¹ , R ² , R ³ and X are as defined above.

Reaction A1

This reaction can be carried out according to a method known per se (for example, see O. Mitsunobu, Synthesis 1981, 1). It is preferred to carry out the reaction in an inert solvent such as dichloromethane, tetrahydrofuran or toluene at -10 ° C to + 50 ° C in the presence of triphenylphosphine and dialkyl azodicarboxylate. If the corresponding propargyl halide or tosylate corresponding to alcohol (2) is available, normal alkylation of the phenol group can also be carried out (see reaction D3).

Reaction B1

This reaction can be carried out according to a method known per se analogous to the method a) described above for the preparation of compounds of formula (I).

Reaction C1

This reaction can be carried out according to a method known per se. It is preferred to carry out the reaction in an inert solvent such as dimethylsulfoxide, N, N-dimethylformamide or the like at 20 ° C to 100 ° C in the presence of a strong base such as potassium tert-butylate or sodium hydride, Et al. [J. Org. Chem. 57, 3531-3535 (1992).

Reaction A2

Can be prepared by methods known per se (for example, DRM Walton and F. Waugh, J. Organomet. Chem. 37, 45 (1972), and KC Nicolaou et al. Am. Chem. Soc., 106, 3548 (1984) "). It is preferred to carry out the reaction in an inert solvent such as dichloromethane at -30 DEG C to 0 DEG C in the presence of a stoichiometric amount of aluminum chloride and bis (trimethylsilyl) -acetylene.

Reaction B2

This reaction can also be carried out according to methods known per se (A. L. Gemal and J. L. Luche, J. Am. Chem. Soc., 103, 5454 (1981)].

Reaction C2

The reaction can also be carried out according to methods known per se.

Reaction D2

This reaction may be carried out according to methods known per se, for example by the method described by JA Katzenellenbogen et al. [J. Org. Chem. 54, 2624 (1991), wherein R ⁴ is tetramethylsilyl, and K. Mori et al., Liebigs Ann. 1991, 529).

Reaction A3

This reaction is carried out analogously to reaction A1.

Starting material 8 is known and is described in L. Jurd et al. Am. Chem. Soc., 81, 4606 (1959).

Reaction B3

The reaction can also be carried out according to methods known per se. Preferably, the compound (9) in an inert solvent such as dichloromethane, tetrahydrofuran or toluene is reacted with a protic acid such as hydrochloric acid, sulfuric acid or trifluoroacetic acid in the presence of water at 20 DEG C to 100 DEG C .

Reaction C3

The selective alkylation of the 4-hydroxy group in compound (11) is carried out in an aprotic polar aprotic solvent such as N, N-dimethylformamide at 0 &lt; 0 &gt; C to 30 &lt; 0 &gt; C by reaction with alkyl iodide in the presence of a weak base such as sodium bicarbonate .

Reaction D3

The reaction can also be carried out according to methods known per se. In an inert solvent such as dimethylsulfoxide, N, N-dimethylformamide or the like in the presence of a strong base such as potassium tert-butylate or sodium hydride at a temperature of 10 ° C to 50 ° C or in the presence of potassium carbonate at 50 ° C to 100 ° C In a polar solvent such as acetone, 2-butanone, or the like.

Reaction E3

This reaction may also be carried out according to methods known per se analogously to process a) mentioned above for a).

Reaction F3

It can be reacted in one step or two steps according to a method known per se. The one-step process (see R. Kanazawa and T. Tokoroyama, "Sysnthesis 1976, 526") is preferably performed at -30 ° C to -10 ° C. The two-step process involves the complete reduction of the corresponding alcohol with aluminum hydride, such as DIBALH or REDAL, followed by re-oxidation with aldehyde using activated manganese dioxide or dimethyl sulfoxide / oxalyl sulfone (Swern) oxidation .

Reaction G3

This reaction corresponds to reaction C1.

Compounds of formula (II) may be prepared from compounds of formula (2) and compounds of formula

Compounds of formula (II) may be prepared from compounds of formula (2) and (14), analogously to reaction A1.

In addition, the preparation of the compounds of formula (II) and (III) is described in the examples.

As described above, the compounds of formula (I) and their pharmaceutically acceptable salts have useful antibacterial properties. They have activity against a number of pathogenic microorganisms such as Staphylococcus aureus , New marshistus carinii and the like, by the activity of the bacteria to inhibit dihydrofolate reductase (DHFR).

By measuring the antimicrobial activity, the degree of inhibition of this enzyme was found. Using the method of Baccanari and Joyner [Biochemistry 20, 1710 (1981)]; See also P. G. Hartman et al. FEB 242, 157-160 (1988).

The IC ₅₀ value (concentration at which the enzyme is inhibited to 50%) is measured by a graph.

The following table shows the inhibitory concentrations obtained for representative members of the group of compounds defined by formula (I) and determined in the test. The IC ₅₀ values (μM) for purified DHFR of the reference strain Staphylococcus aureus ATCC 25923 and purified DHFR of the multi-resistant strain Staphylococcus aureus 157/4696 are provided. The IC ₅₀ value (μM) for the purified DHFR of the opportunistic pathogen, Newmastis carinii, is presented in the third column. The inhibition constant of the trimetop prim (TMP) is also provided as a comparative value.

The product according to the invention can be used as a medicament, for example in the form of a pharmaceutical preparation for enteral or parenteral administration. For example, the product according to the invention may be orally administered in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions; To work in the same form as a suppository; Or may be administered parenterally, such as in the form of injection solutions.

The pharmaceutical preparations may be prepared by any method known in the art, optionally in combination with other materials useful for the treatment of the substances according to the present invention, in combination with suitable non-toxic, inert, therapeutically synthetic solid or liquid carrier materials and, if desired, , Which may be produced in a manner familiar to one of ordinary skill in the art.

Both inorganic and organic carrier materials are suitable as such carrier materials. Thus, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragees and hard gelatine capsules. Examples of suitable carriers for soft gelatine capsules are vegetable oils, waxes, fats and semi-solid and liquid polyols (however, depending on the nature of the active ingredient no carrier is required in the case of soft gelatine capsules). Examples of carrier materials suitable for the production of solutions and syrups include water, polyols, sucrose, phosgene and glucose. Examples of suitable carrier materials for injection solutions are water, alcohols, polyols, glycerol and vegetable oils. Examples of suitable carrier materials for suppositories are natural or hardened oils, waxes, fats and semi-solid or liquid polyols.

Conventional preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavors, salts for varying the osmotic pressure, buffering agents, masking agents and antioxidants are contemplated as pharmaceutical adjuncts.

For oral administration, the compounds of formula (I) and their respective salts are preferably provided as a lyophilizate or anhydrous powder with conventional carriers such as water and isotonic saline for dilution.

The compounds of formula (I) are each characterized by high antimicrobial activity, pronounced synergistic effect in combination with sulfonamides and good tolerance. They inhibit the dihydrofolate reductase of the bacteria and include, for example, sulfoxazole, sulfadimethoxine, sulfamethoxazole, 4-sulfanylamido-5,6-dimethoxy-pyrimidine, Amino-4,5-dimethyl-pyrimidine or sulfaniline, sulfadiazine, sulfammonomethoxine, 2-sulfanilamido-4,5-dimethyl-isoxazole, Has the antimicrobial activity of sulfonamides such as other enzyme inhibitors included in the reaction.

Oral, rectal and parenteral administration are contemplated as medicaments for use in humans when one or more compounds (I) and sulfonamides according to the present invention are combined in this manner. The ratio of compound (I) to sulfonamide can vary widely, and the amount thereof is, for example, 1:40 (parts by weight) to 1: 1 (parts by weight), and the preferable ratio is 1:10 to 1: 2.

Thus, for example, the tablet contains 80 mg of the compound (I) according to the invention and 400 mg of sulfamethoxazole, the child tablet contains 20 mg of the compound (I) according to the invention and 100 mg of sulfamethoxazole; Syrup (per 5 mL) contains 40 mg of compound (I) and 200 mg of sulfamethoxazole.

A daily dosage of about 0.2 g to about 2 g of compound (I) according to the invention is suitable for adults.

The following examples illustrate the invention in more detail. Examples 1 to 4 describe the preparation of starting materials of formulas (II) and (III), while Examples 5 to 10 illustrate the preparation of compounds of formula (I). Temperature is expressed in degrees Celsius.

Example 1

Preparation of compound (2): &lt; EMI ID =

a) 29.3 g of aluminum (III) chloride are suspended in 300 ml of dichloromethane under argon and cooled to -30 &lt; 0 &gt; C. A solution of 44.2 mL of bis (trimethylsilyl) acetylene and 18.3 mL of cyclopropanecarboxylic acid was added over 15 minutes at -30 &lt; 0 &gt; C. The reaction mixture was allowed to warm to -10 &lt; 0 &gt; C, poured into a vigorously stirred mixture of 250 mL of 3N HCl and 500 g of ice, stirred for an additional 10 minutes and finally extracted twice with 750 mL of hexane. The organic phase was washed successively with 750 mL each of saturated NaCl, NaHCO ₃ and NaCl. The organic phase was dried and evaporated. The crude product was distilled at 95 [deg.] C / 14 mbar to give 1-cyclopropyl-3-trimethylsilanyl-prop-2-yn-1-one as a colorless oil.

b) 37.3 g of cerium (III) chloride heptahydrate are added to a solution of 16.6 g of (RS) -1-cyclopropyl-3-trimethylsilanyl-prop-2-yn-1-one in 170 ml of methanol, Stir at &lt; RTI ID = 0.0 &gt; 20 C &lt; / RTI &gt; Subsequently, 1.9 g of sodium borohydride was carefully added in portions to prevent excessive foaming. The resulting white suspension was cooled to 10 &lt; 0 &gt; C, treated with 50 mL of 1N HCl, and then diluted with 150 mL of ice water. The mixture was extracted twice with 400 mL of hexane. The hexane phase was washed with 300 mL of ice water, dried (Na ₂ SO ₄ ) and evaporated. The crude product was distilled at 106 [deg.] C / 14 mbar to give (RS) -1-cyclopropyl-3-trimethylsilanyl-prop-2-yn-1-ol as a yellow oil.

c) 7.8 g of (RS) -1-cyclopropyl-3-trimethylsilanyl-prop-2-yn-1-ol was dissolved in 80 mL of methanol, treated with 0.64 g of potassium carbonate, Lt; / RTI &gt; The methanol was then removed on a rotary evaporator at 200 millibar / 40 占 폚. The residue was taken up in 80 mL of diethyl ether and extracted with 80 mL of ice water. The crude product was distilled at 14 millibar / 60 DEG C (risk of explosion!). (RS) -1-cyclopropyl-prop-2-yn-1-ol as a colorless oil.

d) In analogy to example 1a), methyl 5-oxo-7-trimethyl-silanyl-hept-6-canoate was obtained from the glutaric acid monomethyl ester chloride.

e) In analogy to example Ib), from methyl 5-oxo-7-trimethyl-silanyl-hept-6-inoate was obtained methyl (RS) -5-hydroxy-7-trimethylsilanyl-hept- Acetate.

f) In analogy to example 1c), from methyl (RS) -5-hydroxy-7-trimethylsilanyl-hept-6-oneate was obtained methyl (RS) -5-hydroxy-hept- .

Example 2

Preparation of compound (3): &lt; EMI ID =

A solution of 7.3 g of 3,4-dimethoxy-5-hydroxybenzaldehyde, 6.9 g of (RS) -1-cyclopropyl-3-trimethylsilanyl- g were dissolved in 60 mL of toluene under argon and cooled to 5 &lt; 0 &gt; C. A solution of 6.9 mL of diethyl azodicarboxylate in 20 mL of toluene was slowly added dropwise over 5 minutes at 5 &lt; 0 &gt; C. The resulting reaction mixture was chromatographed directly on silica gel in toluene. 4.2 g (HPLC 80%) of a yellow oil were obtained. This was dissolved in 40 mL of methanol and stirred at 55 [deg.] C with 553 mg of potassium carbonate over 3 hours. Extracted twice with 50 mL each of ethyl acetate and water. For crystallization, it was dissolved in 10 mL of hot ethyl acetate and then diluted with 20 mL of hexane. (RS) -3- (1 -cyclopropyl-prop-2-ynyloxy) -4,5-dimethoxy-benzaldehyde as white crystals.

b) 63.6 g of 3,4-dimethoxy-5-hydroxy-benzoate (E. Spath and H. Roder, Monatsh. fur Chemie, 43, 93 (1923) 38.5 g of (RS) -1-cyclopropyl-prop-2-yn-1-ol and 118 g of triphenylphosphine were dissolved in 600 mL of toluene under argon and cooled to 5 [ A solution of 70 mL of diethyl azodicarboxylate in 150 mL of toluene was slowly added dropwise at 5 [deg.] C over 90 minutes. The mixture was stirred for an additional 1 hour at 5 &lt; 0 &gt; C and 3 hours at 20 &lt; 0 &gt; C. 300 mL of toluene was then distilled off on a rotary evaporator and the resulting suspension was stirred in an ice bath for 30 minutes. The separated triphenylphosphine was filtered off and the filtrate was evaporated. The resulting oil was chromatographed on silica gel using 4: 1, then 3: 1 hexane / ethyl acetate. Diethyl ether and hexane. Methyl (RS) -3- (1-cyclopropyl-prop-2-ynyloxy) -4,5-dimethoxy-benzoate as white crystals.

c) In analogy to example 2a), from methyl (RS) -5-hydroxy-7-trimethylsilanyl-hept-6-oneate was obtained methyl (RS) Dimethoxy-phenoxy) -hept-6-inoate. &Lt; / RTI &gt;

d) In analogy to example 2a), from (RS) -1-octin-3-ol there was obtained (RS) -3,4- dimethoxy- 5- (1-pentyl-prop-2-ynyloxy) &Lt; / RTI &gt;

(RS) -3- (l-isopropyl-prop-2-ynyloxy) -4,5 -Dimethoxy-benzaldehyde. &Lt; / RTI &gt;

f) In analogy to example 2a), from (RS) -5-methyl-1-hexyn-3- ol there was prepared (RS) -3- (l-isobutyl- -Dimethoxy-benzaldehyde. &Lt; / RTI &gt;

Example 3

Preparation of compound (4): &lt; EMI ID =

a) 33.5 g of methyl (RS) -3- (1 -cyclopropyl-prop-2-ynyloxy) -4,5-dimethoxy-benzoate are dissolved in 330 ml of N, N-diethylaniline, Heated to 200 &lt; 0 &gt; C and stirred for an additional 5 hours at 200 &lt; 0 &gt; C. The solvent was distilled at 90 [deg.] C / 1 millibar and the residue was extracted twice with 1.5 L diethyl ether, 1.5 L IN HCl and 1.5 L saturated NaCl, respectively. The resulting oil was purified by silica gel chromatography using toluene, then 9: 1 toluene / ethyl acetate. Diethyl ether and hexane. Methyl (RS) -2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-carboxylate as white crystals.

b1) 2.4 g of (RS) -3- (1 -cyclopropyl-prop-2-ynyloxy) -4,5-dimethoxy-benzaldehyde was dissolved in 20 mL of N, N-diethylaniline, Lt; RTI ID = 0.0 &gt; 200 C &lt; / RTI &gt; for an additional 1 hour. The solvent was distilled at 90 [deg.] C / 1 millibar and the residue was extracted twice with 100 mL diethyl ether, 100 mL 1N HCl and 100 mL saturated NaCl, respectively. The crude product was successively purified by two-fold silica gel chromatography using dichloromethane, then 5: 1 ethyl acetate / hexane. (RS) -2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-carbaldehyde as a brown oil (HPLC 96%).

b2) A solution of morpholine (48 mL) in 50 mL of toluene was added dropwise to 143 mL of an ice-cooled solution of sodium dihydro-bis- (2-methoxyethoxy) aluminate diluted in 200 mL of toluene (3.5 M in toluene) Respectively. The resulting reduced solution was then added to a solution of 46 g of methyl (RS) -2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-carboxylate in 200 mL of toluene at -35 [ Lt; RTI ID = 0.0 &gt; -15 C &lt; / RTI &gt; for an additional 4 hours. The reaction was terminated by careful addition of 40 mL of 3N NaOH and the mixture was allowed to warm. And extracted once with 600 mL of ice water and once with 600 mL of toluene. Chromatography was performed on silica gel using 5: 1 hexane / ethyl acetate. Crystallization from diethyl ether / hexane. (RS) -2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-carbaldehyde as a solid.

c) from (RS) -5- (5-formyl-2,3-dimethoxy-phenoxy) -Formyl-7,8-dimethoxy-2H-1-benzopyran-2-yl) -butyrate.

d) 1.5 g of methyl (RS) -4- (5-formyl-7,8-dimethoxy-2H-1-benzopyran-2-yl) -butyrate was dissolved in 10 ml of tetrahydrofuran under argon, Of NaOH &lt; / RTI &gt; and stirred for 1.5 h at 20 &lt; 0 &gt; C. The reaction mixture was acidified with 9 mL of 1N HCl, saturated with NaCl, and extracted twice with 20 mL of ethyl acetate. The crude product was chromatographed on silica gel in ethyl acetate and chromatographed from 1: 1 toluene / hexane. (RS) -4- (5-formyl-7,8-dimethoxy-2H-1-benzopyran-2-yl) -butyric acid as white crystals.

e) Prepared in analogy to example 3a) from (RS) -7,8-dimethoxy-5- (1-pentyl-prop-2-ynyloxy) 2-pentyl-2H-1-benzopyran-5-carbaldehyde.

f) From analogy to example 3a), (RS) -2-isopropyl-7 (lH-pyrazole-3-carboxaldehyde) , 8-dimethoxy-2H-1-benzopyran-5-carbaldehyde.

g) In analogy to example 3a), from (RS) -2-isobutyl-7 (4-fluorobenzyloxy) , 8-dimethoxy-2H-1-benzopyran-5-carbaldehyde.

Example 4

Preparation of compounds of compound (III)

(RS) -2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-carbaldehyde and 17.5 g of 3-anilinopropionitrile were dissolved in 300 ml of dimethylsulfoxide under argon, Lt; 0 &gt; C and treated portionwise with 13.5 g of potassium tert-butylate. The mixture was then stirred at 10 [deg.] C for 1 hour and at 20 [deg.] C for 5 hours. For work-up, the mixture was poured into 3 L of ice / water and extracted twice with 3 L of ethyl acetate and 3 L of water, respectively. The crude product was purified by silica gel chromatography, eluting with hexane / ethyl acetate in a ratio of 5: 1 to 2: 1, and crystallized from hexane / ethyl acetate. (RS) -3-anilino-2- (2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5- ylmethyl) acrylonitrile as white crystals with a melting point of 140 ° C .

Example 5

1.45 g of guanidine hydrochloride was dissolved in 20 mL of ethanol, stirred with 1.7 g of potassium tert-butoxide for 15 minutes, and then filtered through Dicalite. The filtrate was added to 2 g of (RS) -3-anilino-2- (2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-yl-methyl) acrylonitrile, &Lt; / RTI &gt; The product crystallized spontaneously upon cooling. Recrystallization from 90 mL of ethanol gave (RS) -5- (2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-yl-methyl) pyrimidine- 4-diamine.

Example 6

(RS) -4 (5-formyl-7,8-dimethoxy-2H-1-benzopyran- - [5- (2,4-diamino-pyrimidin-5-ylmethyl) -7,8-dimethoxy-2H- 1 -benzopyran-2-yl] -butyric acid.

Example 7

In analogy to examples 4 and 5, from (RS) -7,8-dimethoxy-2-pentyl-2H-1-benzopyran-5-carbaldehyde there was obtained (RS) -5- -Dimethoxy-2-pentyl-2H-1-benzopyran-5-ylmethyl) -pyrimidine-2,4-diamine.

Example 8

(RS) -5- (2-isopropyl-7-trifluoromethyl-benzyl) -piperidine was prepared in analogy to example 4 and 5 from 2-isopropyl-7,8- dimethoxy- , 8-dimethoxy-2H-1-benzopyran-5-ylmethyl) -pyrimidine-2,4-diamine.

Example 9

(RS) -5- (2-tert-butoxycarbonylamino) -thiazole-4-carboxylic acid was prepared in analogy to examples 4 and 5 from (RS) -2-isobutyl-7,8-dimethoxy- Isobutyl-7,8-dimethoxy-2H-1-benzopyran-5-ylmethyl) -pyrimidine-2,4-diamine.

Example 10

In analogy to examples 4 and 5, tert-butyl 4- [5- (2-cyano-3-phenylamino-allyl) -8-methoxy-2H-chromen-7-yloxy] 4- [5- (2,4-diamino-benzo [b] pyridin-7-yloxy) -butyrate was obtained from tert-butyl 4- -Pyrimidin-5-ylmethyl) -8-methoxy-2H- 1 -benzopyran-7-yloxy] -butyric acid.

Example A

refine

Example B

Claims (9)

A compound of formula (I): &lt; EMI ID = Formula I In this formula, R ¹ is a straight chain C _5-10 -alkyl, a branched chain C _3-5 -alkyl, a C _3-6 -cycloalkyl or a C _3-5 -ω-carboxyalkyl, and R ² and R ³ are each C _1-5 -Alkyl; R ¹ is hydrogen, R ² is C _3-5 -ω-carboxyalkyl, and R ³ is C _1-5 -alkyl. The method according to claim 1, Wherein R ¹ is linear C _5-10 -alkyl, branched chain C _3-5 -alkyl, C _3-6 -cycloalkyl or C _3-5 -ω-carboxyalkyl. (RS) -5- (2-Cyclopropyl-7,8-dimethoxy-2H- 1 -benzopyran- 5-yl- methyl) -pyrimidine- 2,4- (RS) -4- [5- (2,4-diamino-pyrimidin-5-ylmethyl) -7,8- dimethoxy-2H- 1 -benzopyran- (RS) -5- (7,8-Dimethoxy-2-pentyl-2H-1-benzopyran-5-yl-methyl) -pyrimidine- (RS) -5- (2-isopropyl-7,8-dimethoxy-2H-1-benzopyran- 5-ylmethyl) -pyrimidine- 2,4-diamine, and Methoxy-2H-1-benzopyran-7-yloxy) -butyric acid. &Lt; / RTI &gt; A compound of formula (II) (II) In this formula, R ¹ , R ² and R ³ are as defined in claim 1, respectively. A compound of formula (III) (III) In this formula, R ¹ , R ² and R ³ are each as defined in claim 1, and X is a leaving group. 4. The method according to any one of claims 1 to 3, A compound for use as a medicament. a) reacting a compound of formula (II): EMI5.1 b) reacting guanidine with a compound of formula (III) &lt; EMI ID = Lt; RTI ID = 0.0 &gt; of: &lt; / RTI &gt; (II) (III) In this formula, R ¹ , R ² and R ³ are each as defined in claim 1, and X is a leaving group. 7. A medicament for the treatment of infectious diseases, comprising a compound according to any one of claims 1 to 3 and a therapeutically inert carrier. An antibiotically-active agent comprising a compound according to any one of claims 1 to 3 and a therapeutically inert carrier.